Toll-like Receptors in Hematology: Comparison
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Toll-like receptors (TLR) belong to the pattern recognition receptors (PRR). TLRs are primarily expressed in hematopoietic cells. TLRs also direct the formation of blood cellular components and make a contribution to the pathogenesis of certain hematopoietic malignancies. 

  • toll-like receptors
  • immunotherapy
  • cancer
  • leukemia
  • Hematology

1. Introduction

1.1. Pattern Recognition Receptors (PRR)

Pattern recognition receptors (PRR) play a major role in the innate immune response. These PRRs are a large group of receptors that can be located on the surface of or inside cells—most often in the membrane of lysosomes, mitochondria, and endoplasmic reticulum or in the cytoplasm [6][1]. Most PRRs in the innate immune system can be classified into five types based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), C-type lectin receptors (CLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs) [7][2]. They are localized not only on immune cells, including effector immune cells (macrophages, dendritic cells, granulocytes, and lymphocytes), progenitor cells (HSPCs), and the hematopoietic stem but also on non-specialized, non-immune epithelial and endothelial cells or fibroblasts. They initiate an intracellular signaling cascade necessary to keep tissue homeostasis and remove potentially dangerous pathogens. However, these TLR functions can be damaging and even lead to death [8][3].

1.2. Toll-like Receptors (TLR) Family

Toll-like receptors belong to the pattern recognition receptors, and they play a prominent role in the development and maintenance of the immune system. There are at least 10 members of the human Toll-like receptor (TLR) family [9][4]. The extracellular TLR groups (TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10) are expressed on the plasma membrane, whereas the intracellular TLR groups (TLR3, TLR7, TLR8, and TLR9) are expressed in the endosome and endoplasmic reticulum. TLR4 is found on the plasma membrane as well as in the intracellular compartments [10][5]. The differential expression of TLRs forms the basis for many key immune responses. For example, monocytes, NK cells, mast cells, neutrophils, eosinophils, B-cells, and T-cells all have characteristic TLR expression patterns with a specific immunological effect. The expression of TLRs is modulated rapidly in response to pathogens, cytokines, and environmental stresses [11][6]. Generally, the TLRs expressed on the cell surface recognize microbial membrane proteins, lipids, and lipoproteins, whereas endosomal TLRs recognize microbial- and self-derived nucleic acids [12][7].

1.3. Structure of TLRs

Toll-like receptors belong to the type I transmembrane family, which is characterized by the extracellular leucine-rich repeats (LRR) for the recognition of pathogen-associated molecular patterns (PAMPs)/damage-associated molecular patterns (DAMPs), transmembrane domains, and intracellular toll-interleukin 1 receptor (TIR) domains for the activation of downstream signal transduction pathways [13,14][8][9]. Each LRR consists of a β strand and an α helix connected by loops. The LRR domains consist of 19–25 tandem LRR motifs, 24–29 amino acids in length, which contain the motif XLXXLXLXX and also other conserved amino acid residues (XØXXØXXXXFXXLX; Ø = hydrophobic residue) [15][10].

2. Role of TLRs in Hematopoiesis

The formation of blood components is a self-regenerative process that occurs all throughout human life, starting during fetal development [49][11]. All blood cell types originate from hematopoietic stem cells (HSCs). Hematopoietic stem cells mostly occupy the bone marrow, although some of them circulate in the blood stream or tissues. The most important positive marker for human hematopoietic and progenitor stem cells is the CD34 antigen. TLRs not only influence the adaptive immune system but also the circulation, differentiation, and action of HSCs [50][12].
Studies showed that human bone marrow hematopoietic progenitor cells constitutively express several toll-like receptors (in particular TLR4, TLR7, and TLR8) [51][13] and respond to receptor involvement [51,52,53,54][13][14][15][16]. Separate experiments showed that TLR9 was also displayed by CD34+ progenitor cells [51][13]. Other analyses revealed that many TLRs such as TLR9 and TLR10 were mostly linked to CD19+ B-cells, whereas others—TLR2, TLR4, TLR8—were expressed to the utmost in CD14+ mononuclear cells [55][17]. TLR7 and TLR8 can primarily be found in the myeloid cell population, including neutrophils, monocytes, and DCs with a scarce expression of hematopoietic stem and progenitor cells (HSPCs) [56][18]. Human pDC mainly expresses TLR7 and TLR9, whereas mDC expresses most TLR except TLR7, TLR8, and TLR9 [54][16]. Moreover, the common DC progenitor (CDP) expresses elevated levels of TLR2 and TLR9 and moderate levels of TLR4 and TLR7 in comparison to other HSPCs [53][15]. Once PAMPs from the restricted origin of an infection have spread systemically, they can span the bone marrow and be sensed by hematopoietic progenitor cells’ TLRs. TLR signaling is able to have an influence over HSPCs both by cell autonomous and cell non-autonomous mechanisms [57][19]. Firsthand stimulation of TLR2, TLR4, and TLR7/8 causes multipotent HSPCs, common myeloid progenitors (CMPs), and granulocyte–macrophage progenitors (GMPs) to convert to monocytes, macrophages, and DCs at the cost of other progenitors [51,53,56][13][15][18]. CD34+ cells incubated with TLR7/8-specific agonists such as small interfering RNAs (siRNA-27), R848 (resiquimod), and loxoribine can differentiate into myeloid cells (early as well as late granulo-monocytic progenitor cells) [51,53,54][13][15][16]. A significant cell population of the CD34+ progenitor increased the expression of CD11c (deliberated as one of the markers of myeloid DC in humans) and CD13 (the early myeloid marker) [51][13]. Other studies showed that treatment with R848 induces considerable heightening in bone marrow (BM) resident cDC, a lowering in the common dendritic cells’ progenitors and pre-DCs, and upregulation of CD83 (DC activation marker); treatment prompted an expansion of phenotypic HSC with a decreased repopulating potential and HSPC mobilization [56][18]. Another study found that although TLR-induced lineage skewing of upstream progenitors can give rise to multiple cells, in the case of BM DC-restricted progenitors (CDPs) TLR induction results in their mobilization via down-regulation of chemokine receptor CXCR4 expression and recruitment to lymph nodes through up-regulation of chemokine receptor CCR7 expression [53][15]. TLR7 and TLR8 signaling in DC is not required for the increase in DCs or HSPCs or HSPC mobilization [56][18].

3. TLR Agonists in Hematology

3.1. TLR Agonists as a Treatment for Lymphomas

Lymphoma treatment options include skin-directed therapies such as topical steroids, chemotherapy, retinoids, phototherapy, and radiotherapy. For the advanced stage, systemic treatments by biological or targeted therapies are used [58,59][20][21]. A promising, new approach is represented by TLR agonists that can stimulate the immune system to induce an anti-cancer response.
In a phase 1 randomized controlled trial, the efficacy of a TLR7/8 agonist was evaluated. Twelve patients with stage IA-IIA cutaneous T-cell lymphomas (CTCL) took part in this clinical trial. They applied 0.03% or 0.06% topical resiquimod gel to a limited number of skin lesions over a period of several weeks. Clinical improvement was observed in 92% of patients, with all treated lesions clearing in 33% of patients. A reduction in the percentage of malignant T-cell clones was observed in 90% of the biopsy lesions that were in post-treatment. The successful response to treatment was associated with the increased production of IFN-γ and TNF-α by CD4+ T cells and the enhancement of NK cells’ function. Increased CD80 expression was also observed; however, the DC maturation in peripheral blood did not correlate with an increased clinical response. Three patients had a response in their untreated lesions, suggesting that systemic antitumor immunity may develop after topical therapy with these drugs [60][22].
Previous in vitro observations demonstrated that TLR7/8 agonists stimulate the peripheral blood mononuclear cells (PBMC) of patients with CTCL leukemia and Sézary syndrome, producing high levels of cytokines. The TLR7 agonist increased the synthesis of IFN-α, while the TLR8 agonist increased the synthesis of IL-12 and IFN-γ. The main function of induced cytokines is to enhance the cytolytic functions of NK cells and T cells by upregulating CD68 and CD25 expression. In addition, they stimulate the Th1-mediated immune response and reinforcement of cellular immunity, key elements of effective anti-cancer response. [61][23]. Synergistically enhancing the immune system is possible by combining IFN-γ or IL-15 with a TLR7/8 agonist [62][24].
The published data on the use of imiquimod in the treatment of CTLC are case reports or series involving a small number of patients (Table 1). Lesions resolved completely without recurrence within several years of follow-up [63,64][25][26]. The severe adverse effects of topical therapy with TLR7/8 agonists were usually limited to the skin. Patients reported redness, local irritation, and, in some cases, flu-like symptoms such as muscle aches, headaches, and an increased temperature. Most side effects resolved spontaneously or after a short break in treatment [60,65,66][22][27][28].
Table 1.
Case series’ reported results on the use imiquimod in the treatment of cutaneous lymphoma.
Age/Sex

of Patients		 Disease Intervention/ Treatment Therapy Effect Adverse Events References
66 years/

Female Adult T-cell lymphoma Imiquimod 5%

cream		 Nearly complete resolution of the plaque Not reported Messer et al.

[63]		Messer et al.

[25]
65 years/

Female Mycosis

Fungoides		 Imiquimod 5% cream Nearly complete resolution of the plaques Significant irritation,

flu-like symptoms		 Lewis et al.

[65]		Lewis et al.

[27]
77 years/

Female Anaplastic large cell lymphoma Imiquimod 5% cream

Mupirocin 2%

cream		 Complete resolution of the plaque Not reported Kubicki et al. [64]Kubicki et al. [26]
68 years/

Male Mycosis Fungoides Imiquimod 5% cream

Bexarotene 150mg		 Complete resolution of the plaques Not reported Lewis et al.

[65]		Lewis et al.

[27]
21 years/

Female Folliculotropic Mycosis

Fungoides		 Imiquimod 5% cream Complete resolution of the plaque Site irritation, pruritus, ulceration Schalabi et al. [67]Schalabi et al. [29]
These results are particularly promising regarding the potential future use of TLR7/8 agonists in the treatment of lymphomas. Resiquimod and imiquimod can be effective alternatives in the treatment of skin lesions. They are safe, well-tolerated, and highly effective drugs.

3.2. TLR Agonists as a Treatment for Leukemia

There are some in vivo and in vitro studies supporting the efficacy of TLR agonists for enhancing and directing the immunological response against specific antigens in leukemia.
Specific TLR agonists may be growth-inhibiting and pro-apoptotic in some myeloid leukemia cell lines. Imiquimod can lead to the detention of the cell cycle and the activation of apoptosis of cancer cells [68][30]. A similar effect was demonstrated by resiquimod [69][31]. TLR7/8 agonists promote the induction of AML cells by increasing the expression of mature myeloid markers, which leads to an enhanced immune response [68,69][30][31].
Different cells of the immune system are involved in the anti-cancer response. An increasing role in the therapy of hematological malignancies is attributed to DC cells and their subsets. They act as one of the most effective antigen-presenting cells and activate T lymphocytes, participating in the regulation of innate and adaptive immune response [70,71,72][32][33][34]. The use of a TLR7/8 agonist leads to higher CD40 expression and an increase in INF-β production by pDC. Treatment with INF-β led to the upregulation of CD38 expression and a greater cytotoxicity of AML cells in the presence of daratumumab (anti-CD38 antibody) [73][35]. Another study about developing a dendritic cell vaccine to be used for therapy of minimal residual disease in acute myeloid leukemia assessed the uptake of apoptotic leukemic cells by monocyte-derived DC (MoDC) and DC after stimulating the TLR7/8 receptor. Resiquimod increased tumor cell uptake by DC in vitro; however, in combination with cocktail of cytokines, it interfered with the maturation process and the ability of MoDC to migrate and stimulate T lymphocytes, therefore did not find therapeutic use [74][36].
The TLR7/8 agonist, TNF-α, and lipopolysaccharide can induce an increase in cytotoxic T cells (CTL) production and stimulate activation of DC in an in vitro culture. Single reagents induced a significantly higher expression of CD80, CD86, CD83, CD40, CD54, and HLA-DR in AML cells. The best results were achieved using a combination of all three reagents: CD80 expression on AML cells was the highest. Stimulated and activated CTL released significantly higher levels of IFN-γ and showed a greater cytotoxicity compared to the control sample. These results indicate that the combination of a TLR7/8 agonist, TNF-α, and lipopolysaccharide induces a significantly enhanced effect of antigen presentation by AML-DC [75][37].
NK cells are a new form of cell-mediated immunotherapy for patients with AML. Their differentiation and cytotoxicity are induced by the cytokines (IFN-γ, IL-12, IL-15, and IL-18), with production that is differently regulated by TLR agonists [76,77][38][39]. Resiquimod stimulates the significant production of IFN-γ by NK cells, of CD8+ T cells, and of IL-12 by monocytes [78,79][40][41]. Incubation of AML cells and PBMC with a TLR7/8 agonist can induce IFN-γ production, resulting in strong NK cells’ activation and increased cytotoxicity to AML cells [80][42]. Other studies also confirmed significantly increased levels of IFN-γ, TNF-α, and GM-CSF in R848-stimulated NK cells’ supernatants and an enhancement in their cytotoxicity [81][43].
With a TLR7 agonist, it is possible to enhance the efficacy of chemotherapy or facilitate the killing of cytotoxic T cells through increased tumor immunogenicity [82][44]. The effects of TLR7 stimulation in CLL cells vary between studies. Most of them confirm the expression of co-stimulatory molecules, the production of pro-inflammatory cytokines, and an increased sensitivity to killing by cytotoxic effectors [83,84][45][46]. Another study showed a synergistic effect between TLR7 and cladribine. The percentage of necrotic cells after imiquimod application was higher by 3.8% compared to the medium alone, and the effect was enhanced by the addition of a chemotherapeutic agent. The TLR7 agonist led to a significant increase in IL-6 and IL-10 and a decrease in IL-17A. However, there was no increase in the CD80, CD86, CD40, or CD95 on CLL cells [85][47].
Other studies suggested that the stimulation of TLR7/8 receptors in CLL leads to improved viability of leukemic cells. Specific TLR-7 ligands induce a marked increase in NO production in B-CLL cells, which has an anti-apoptotic effect [86][48].
Preclinical studies showed that TLR agonists can effectively treat AML and inhibit cancer cell proliferation. However, their potential in the treatment of CLL is questionable and requires further research.

3. Negative Aspects of TLR Signaling and Its Role in Hematopoietic Diseases

HSCs of mice treated repetitively with small doses of LPS expressed features of damage. Cells were not able to withhold quiescence; after transplantation, they were found to be myeloid skewed, and, additionally, they were not sustained in serial transplants and developed lymphoid progenitors with unsatisfying levels of E47 transcription factor [87][49]. Persistent TLR signaling may have subsequent consequences such as long-term harm of the self-renewal potential and functional solidity of HSC [87,88][49][50].
In patients with myelodysplastic syndromes, especially lower-risk MDS, TLR signaling is magnified. Such a phenomenon is due to a combination of genetic and epigenetic changes that influence various components of the TLR signaling pathway and have both direct and indirect effects on precancerous and cancerous cells, for instance, marked cell-death and ineffective hematopoiesis [50][12]. Hyper-activated innate immune signaling, enhanced TLR signaling in CD34+ HSPCs, and loss of TLR pathway repressors have been observed [89,90,91,92,93,94][51][52][53][54][55][56]. Various genes, known to be regulated by TLRs, are overexpressed or aberrantly activated in patients’ BM CD34+ cells in contrast to healthy individuals [89,90,91,92,93][51][52][53][54][55]. Patients’ hematopoietic and progenitor stem cells displayed sustained myeloid expansion upon continuous inflammation [93][55]. MyD88 expression levels have a tendency to be heightened in patients with lower-risk MDS [91][53]. Moreover, the activating mutation of MyD88 correlates with lymphoid malignancies [57,91][19][53].
In addition to their link to the immune cells, TLRs are also found in cancer cells, where TLR7/8 signaling is not very easy to understand and is related to either beneficial or harmful outcomes.

3.1. B-Lymphoid Malignancies

TLR7 expression is associated mostly with B cells, DCs, and monocytes, whereas TLR8 expression is associated mostly with DCs, monocytes, and granulocytes [95][57]. B cells express a number of toll-like receptors (predominantly TLR1, TLR6, TLR7, TLR9, TLR10), and a TLR-initiated reaction in such cells leads to expansion, an anti-apoptosis effect, and PC differentiation [96][58]. Other studies show that TLR7 and TLR9 play a vital role in the autoreactive B-cells’ activation [97][59].
B-cell homeostasis is largely regulated by B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) ligands and their receptors (B-cell maturation antigen/BCMA, transmembrane activator and calcium-modulator and cytophilin ligand interactor/TACI, and B cell-activating factor receptor/ BAFF-R). The BAFF–APRIL system is greatly engaged with the selection of conditions such as multiple myeloma/ MM (since BCMA promotes myeloma growth in BM) and autoimmune diseases. Experiments showed that pDCs in human blood carry the BCMA protein and display it on the cell surface upon TLR engagement (TLR7/8 agonist R848 and TLR9 agonist CpG-A). Agonists induced the release of serum B-cell maturation antigen (sBCMA) from pDCs and IFN-α (in comparison with the TLR9 agonist, R848 did not influence the levels of interferon). Drugs targeting such receptors are under development and can have positive outcomes on the treatment of lymphoid neoplasms [98][60].
TLRs were proclaimed to have been found on freshly isolated myeloma cells and the MM cell lines, with their expression being notably higher than in normal plasma cells [96,99,100,101][58][61][62][63]. TLR-specific ligands induce intensified proliferation, endurance, cytokine and chemokine excretion, induction of apoptosis or protection from it, drug resistance, and the immune escape of the MM cell lines, in some measure due to autocrine interleukin-6 production [96,102][58][64]. Human myeloma cell lines (HMCL) express a broad range of TLRs at the gene and protein levels, with TLR1, TLR4, TLR7, TLR8, and TLR9 being the most detectable [99,100][61][62]. Novel studies found TLR7 to be the most frequently expressed of all the TLRs in the MM cell lines, with some of its ligands such as loxoribine and R848 inhibiting apoptosis and promoting the proliferation of cell survival [101][63].
Furthermore, TLRs are associated with CLL. Leukemic cells from CLL patients express TLR1, TLR2, TLR6, TLR7, TLR9, and TLR10. The sequence of expression is similar to the one detected in memory CD19+ CD27+ B-cells, although TLR-2 and TLR-7 are expressed at higher levels in B-CLL [103,104][65][66]. After stimulation of B-CLL cells with TLR agonists, the upregulation of activation markers (CD40, CD86, CD80, and HLA-DR molecules) was observed, just like in normal B-lymphocytes. In contrast to other agonists, stimulation by loxoribine has only a negligible effect on leukemic cells’ survival (induction of apoptosis as well as proliferation of a subpopulation of B-CLL cells) and has no effect on normal B cells, while cancerous cells produce significantly higher levels of TNFα. TLR-9 and TLR-7 stimulation of CD38 B-CLL leads to an increased numbers of cells expressing CD38 (surface protein with expression that increases upon normal B-cell activation, a marker of disease aggression in B-CLL) on sorted B-CLL cells [104][66].
MyD88 mutations arise in a number of human malignancies such as Waldenstrom macroglobulinemia (WM), CLL, cutaneous B-cell lymphoma (CBCL), and primary central nervous system lymphoma (PCNSL) [105,106][67][68]. Improper activation of TLRs has been featured in activated B-cell-type diffuse large B cell lymphoma (ABC-DLBCL), which has a pathogenesis that centers around constitutively active NF-κB. The MyD88 L265P oncoprotein attaches to TLR7 and TLR9, increasing the signals from such receptors as a consequence. Suppression of TLR7 or TLR9 promotes apoptosis among ABC-DLBCL cell lines. A reduction in the proteins essential for TLR7 and TLR9 trafficking and signaling, as well as the pharmacological inhibition of receptors’ function, reduces the survival of cancerous lines. A better understanding of the oncogenic mechanisms of MyD88 mutations provides the reasoning for targeting TLR7 and TLR9 signaling for ABC-DLBCL therapy [105][67].
The connection between enhanced TLR expression and hematopoietic malignancies indicates there are therapeutic benefits from TLR signaling repression. Various novel TLR pathway inhibitors emerge, such as HJ901 (TLR7/9 inhibitor) [107][69] and CA-4948 (IRAK4 inhibitor) [108][70]. They are becoming the therapeutic targets for the treatment of MDS, AML, ABC-DLBCL, and non-Hodgkin’s lymphoma, among other diseases.

3.2. Myeloid Malignancies

AML blasts express a vast range of TLRs [69,109,110][31][71][72]. Higher mRNA expression of TLR pathway molecules, the upregulation of negative TLR signaling pathway regulators and NF-κB inhibitors, and lower expression of transcriptional regulators were observed, which are thought to correlate with increased neoplastic cells’ survival [109][71]. A number of TLRs are also expressed in AML cell lines, and particular receptor agonists influence some cell lines and induce growth inhibitory and apoptotic effects [69,109][31][71]. R848 restrains the growth of human AML cells in immunodeficient mice, within a direct effect on cancerous cells [109][71]. TLR8 stimulation can have a straight anti-leukemia activity as well. Treatment with R848, mediated through TLR8, prompts terminal differentiation and inhibits AML proliferation; in addition, it harms cell and colony growth in vitro and tumor formation in vivo [69][31]. Different studies showed that in comparison to other TLR agonists, imiquimod profoundly delays the propagation of all tested AML cell lines, and an aggregation of cells in the M phase was observed [110][72].
The targeting of innate immune signaling, particularly TLRs, is an attractive new therapeutic approach, although the specific contribution of such signaling to disease progression is not clear.

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